PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells

Anna Maria Jegg, Toby M. Ward, Elizabeth Iorns, Nicholas Hoe, Jinyao Zhou, Xiaofei Liu, Sharat Singh, Ralf Landgraf, Mark D. Pegram

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2-amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER-/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels.

Original languageEnglish (US)
Pages (from-to)683-692
Number of pages10
JournalBreast cancer research and treatment
Volume136
Issue number3
DOIs
StatePublished - Dec 1 2012

Keywords

  • Breast cancer
  • Clinical drug resistance
  • ERBB2-targeted therapy
  • Lapatinib
  • mTOR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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